Lenalidomide With Standard-Dose or Low-Dose Dexamethasone in Treating Patients With Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00098475
First received: December 7, 2004
Last updated: December 5, 2013
Last verified: December 2013
  Purpose

This randomized phase III trial is studying lenalidomide and low-dose dexamethasone to see how well it works compared to lenalidomide and standard-dose dexamethasone in treating patients with multiple myeloma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide and thalidomide may also stop the growth of multiple myeloma by blocking blood flow to the cancer. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide, thalidomide, and dexamethasone together may kill more cancer cells.


Condition Intervention Phase
Multiple Myeloma
Drug: lenalidomide
Drug: dexamethasone
Drug: thalidomide
Drug: acetylsalicylic acid
Drug: Coumadin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase III Study of CC-5013 Plus Dexamethasone Versus CC-5013 Plus Low Dose Dexamethasone in Multiple Myeloma With Thalidomide Plus Dexamethasone Salvage Therapy for Non-Responders

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Proportion of Patients With Objective Response (First Phase, Step 1) [ Time Frame: Assessed every 4 weeks for 16 weeks during Step 1 ] [ Designated as safety issue: No ]

    Objective response is defined as either complete response (CR) or partial response (PR). Patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow are considered to have CR. PR requires all the following: (1) ≥50% reduction in the level of the serum monoclonal paraprotein. (2) Reduction in 24-hour urinary light chain excretion either by ≥90% or to <200 mg. (3)For patients with non-secretory (or oligosecretory) myeloma only, a ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy must be documented. (4)50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination). (5) No increase in the number or size of lytic bone lesions (development of a compression fracture does not exclude response).

    As the expansion phase was a substudy terminated early with only 7 patients enrolled, the clinical results presented are mainly for the first phase only.



Secondary Outcome Measures:
  • Proportion of Patients With Objective Response (First Phase, Step 2) [ Time Frame: Assessed every 4 weeks for 16 weeks during Step 2 ] [ Designated as safety issue: No ]

    Objective response is defined as either complete response (CR) or partial response (PR). Patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow are considered to have CR. PR requires all the following: (1) ≥50% reduction in the level of the serum monoclonal paraprotein. (2) Reduction in 24-hour urinary light chain excretion either by ≥90% or to <200 mg. (3)For patients with non-secretory (or oligosecretory) myeloma only, a ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy must be documented. (4)50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination). (5) No increase in the number or size of lytic bone lesions (development of a compression fracture does not exclude response).

    As the expansion phase was a substudy terminated early with only 7 patients enrolled, the clinical results presented are mainly for the first phase only.



Enrollment: 452
Study Start Date: October 2004
Estimated Study Completion Date: March 2014
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (First phase, lenalidomide, dexamethasone)
Patients receive oral lenalidomide once daily on days 1-21, oral aspirin (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20. Patients with minimal response or no response after 4 cycles of treatment could register for Step 2 treatment with thalidomide and high-dose dexamethasone. Thalidomide was given orally once daily on days 1-28, and dexamethasone once daily on days 1-4, 9-12, and 17-20 for 4 cycles.
Drug: lenalidomide
Given orally (PO)
Other Names:
  • CC-5013
  • IMiD CC-5013
  • Revlimid
  • Revimid
Drug: dexamethasone
Given PO
Other Names:
  • Decadron
  • Hexadrol
  • Dexameth
  • Dexone
  • DXM
Drug: thalidomide
Given PO
Other Names:
  • (d,1)-N phthalidoglutarimide
  • Thalomid
Drug: acetylsalicylic acid
Given PO
Other Names:
  • Aspirin
  • ASA
  • Ecotrin
  • Empirin
Experimental: Arm II (First phase, lenalidomide, low-dose dexamethasone)
Patients receive oral lenalidomide and acetylsalicylic acid as in arm I and low-dose oral dexamethasone once daily on days 1, 8, 15, and 22. Patients with minimal response or no response after 4 cycles of treatment could register for Step 2 treatment with thalidomide and low-dose dexamethasone. Thalidomide was given orally once daily on days 1-28, and dexamethasone once daily on days 1, 8, 15, and 22 for 4 cycles.
Drug: lenalidomide
Given orally (PO)
Other Names:
  • CC-5013
  • IMiD CC-5013
  • Revlimid
  • Revimid
Drug: dexamethasone
Given PO
Other Names:
  • Decadron
  • Hexadrol
  • Dexameth
  • Dexone
  • DXM
Drug: thalidomide
Given PO
Other Names:
  • (d,1)-N phthalidoglutarimide
  • Thalomid
Drug: acetylsalicylic acid
Given PO
Other Names:
  • Aspirin
  • ASA
  • Ecotrin
  • Empirin
Active Comparator: Arm III (Expansion; lenalidomide, dexamethasone, aspirin)
Patients receive oral lenalidomide once daily on days 1-21, oral aspirin (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20. After 4 cycles of treatment, patients may discontinue treatment or continue until progression.
Drug: lenalidomide
Given orally (PO)
Other Names:
  • CC-5013
  • IMiD CC-5013
  • Revlimid
  • Revimid
Drug: dexamethasone
Given PO
Other Names:
  • Decadron
  • Hexadrol
  • Dexameth
  • Dexone
  • DXM
Drug: acetylsalicylic acid
Given PO
Other Names:
  • Aspirin
  • ASA
  • Ecotrin
  • Empirin
Experimental: Arm IV (Expansion; lenalidomide, dexamethasone, coumadin)
Patients receive oral lenalidomide once daily on days 1-21, oral aspirin (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20. After 4 cycles of treatment, patients may discontinue treatment. For patients continuing therapy beyond 4 cycles, coumadin was discontinued and aspirin was given instead.
Drug: lenalidomide
Given orally (PO)
Other Names:
  • CC-5013
  • IMiD CC-5013
  • Revlimid
  • Revimid
Drug: dexamethasone
Given PO
Other Names:
  • Decadron
  • Hexadrol
  • Dexameth
  • Dexone
  • DXM
Drug: Coumadin
Given PO
Other Name: warfarin

  Hide Detailed Description

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the response rate and toxicity of CC-5013 (lenalidomide) plus dexamethasone (standard dose) versus CC-5013 plus low dose dexamethasone in patients with newly diagnosed myeloma at any time in the first 4 cycles of treatment and to determine if CC-5013 plus low dose dexamethasone will have similar response rate with lower toxicity (First Phase).

SECONDARY OBJECTIVES:

I. To evaluate the response rate of thalidomide plus dexamethasone (Thal/Dex) in patients with newly diagnosed myeloma who do not achieve a complete or partial response at any time in the first 4 cycles with the CC-5013 and dexamethasone combination in either of the two arms (First Phase).

II. To study the effect of CC-5013 on bone marrow microvessel density and angiogenesis grade, on plasma cell labeling index (PCLI), and on the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the marrow (First Phase).

III. To study the effect of CC-5013 and dexamethasone on bone marrow mesenchymal progenitor cells (MPCs) (First Phase).

IV. To evaluate in a separate expansion phase the efficacy of aspirin (325 mg/day) versus Coumadin (dose adjusted to maintain a target international normalized ratio (INR) of 2-3) in preventing deep vein thrombosis (DVT) in patients with newly diagnosed myeloma receiving CC-5013 plus standard dose dexamethasone. This separate expansion phase of the trial that will start after accrual to the first phase of the trial testing the primary objective listed above is completed.

OUTLINE: This was an open label, randomized phase III study of CC-5013 (lenalidomide, Revlimid ®) plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma patients. Beginning when accrual for the primary objective was completed, a substudy comparing two anticoagulation regimens each given with high-dose dexamethasone opened. Hereafter, the original design is referred to as the 'First Phase' and the substudy, the 'Expansion Phase'. The purpose of the expansion phase is to determine if anticoagulation with coumadin to a target INR of 2-3 will be significantly superior to aspirin 325 mg/day in preventing DVTs (and related thromboembolic events) in patients with newly diagnosed myeloma.

The expansion phase opened in January 2007. After the first pre-planned interim analysis, evidence of an overall survival advantage on the low dose arm prompted early release of survival data, and the DMC recommended that the expansion phase close and required all patients switch to the low-dose dexamethasone regimen. As the expansion phase was terminated early with only 7 patients enrolled, the clinical results presented are mainly for the first phase only. Toxicity data are available for both the first phase and the expansion phase.

Patients were randomized to 1 of 2 treatment arms in the first phase.

First Phase:

Arm I: Patients receive oral lenalidomide once daily on days 1-21, oral aspirin (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20. Patients with minimal response or no response after 4 cycles of treatment could register for Step 2 treatment with thalidomide and high-dose dexamethasone. Thalidomide was given orally once daily on days 1-28, and dexamethasone once daily on days 1-4, 9-12, and 17-20 for 4 cycles.

Arm II: Patients receive oral lenalidomide and acetylsalicylic acid as in arm I and low-dose oral dexamethasone once daily on days 1, 8, 15, and 22. Patients with minimal response or no response after 4 cycles of treatment could register for Step 2 treatment with thalidomide and low-dose dexamethasone. Thalidomide was given orally once daily on days 1-28, and dexamethasone once daily on days 1, 8, 15, and 22 for 4 cycles.

Expansion Phase: Patients registered after Addendum #6 were randomized to either Arm III or Arm IV.

Arm III: Patients receive oral lenalidomide once daily on days 1-21, oral aspirin (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20. After 4 cycles of treatment, patients may discontinue treatment or continue until progression.

Arm IV: Patients receive oral lenalidomide once daily on days 1-21, oral aspirin (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20. After 4 cycles of treatment, patients may discontinue treatment. For patients continuing therapy beyond 4 cycles, coumadin was discontinued and aspirin was given instead.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 2 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be diagnosed with symptomatic multiple myeloma within the past 90 days confirmed by the following:

    • Bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma which must be obtained within 4 weeks prior to randomization
    • Measurable levels of monoclonal protein (M protein): >= 1.0 g/dL on serum protein electrophoresis or >= 200 mg of monoclonal light chain on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to randomization Please note that if both serum and urine m-components are present, both must be followed in order to evaluate response
  • Hemoglobin > 7 g/dL
  • Platelet count > 75,000 cells/mm^3
  • Absolute neutrophil count > 1000cells/mm^3
  • Creatinine < 2.5 mg/dL and creatinine clearance (measured or calculated) >= 60 mL/min
  • Bilirubin < 1.5 mg/dL
  • Serum glutamate pyruvate transaminase (SGPT; ALT) and serum glutamate oxaloacetate transaminase (SGOT; AST) =< 2.5 times the upper limit of normal
  • Prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day; prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted
  • Prior palliative and/or localized radiation therapy is permitted provided at least 4 weeks have passed from date of last radiation therapy to date of registration; patients with prior solitary plasmacytoma treated with radiation therapy with curative intent are eligible if the disease has now progressed to active multiple myeloma meeting all the eligibility criteria for this protocol
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to starting course 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method (IUD, birth control pills, tubal ligation or partner's vasectomy) and one additional effective method (condom, diaphragm or cervical cap); FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy starting 4 weeks prior to and while taking CC5013 or thalidomide and for four weeks after discontinuing this therapy. A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
  • Patients with a history of prior malignancy are eligible provided there is no active malignancy and a low expectation of recurrence within 6 months

Exclusion Criteria:

  • Prior systemic therapy with the exception of bisphosphonates for multiple myeloma
  • Prior glucocorticosteroid therapy for the treatment of multiple myeloma
  • Active, uncontrolled seizure disorder. Patients must have had no seizures in the last 6 months
  • Uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson Syndrome
  • Patients with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible
  • Grade 2 or higher peripheral neuropathy due to other medical conditions at the time of randomization
  • Active, uncontrolled infection
  • History of current or previous deep vein thrombosis or pulmonary embolism regardless of whether or not the patient is receiving anticoagulation therapy

    • For patients registered prior to activation of Addendum # 6; patients must be willing and able to take prophylaxis with either aspirin at 325 mg/day or alternative prophylaxis with either low molecular weight heparin or Coumadin
    • For patients registered after activation of Addendum # 6; patients entering the expansion phase of the protocol, which tests anticoagulant prophylaxis, must be able and willing to be randomized between aspirin at 325 mg/day and Coumadin
  • Pregnant or breastfeeding
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00098475

Locations
United States, Massachusetts
Eastern Cooperative Oncology Group
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Investigators
Principal Investigator: S. Vincent Rajkumar Eastern Cooperative Oncology Group
  More Information

Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00098475     History of Changes
Other Study ID Numbers: NCI-2012-03150, E4A03, U10CA021115, CDR0000404161
Study First Received: December 7, 2004
Results First Received: August 30, 2013
Last Updated: December 5, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
multiple myeloma
cc-5013
dexamethasone
thalidomide

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Aspirin
Dexamethasone acetate
Dexamethasone
BB 1101
Warfarin
Dexamethasone 21-phosphate
Lenalidomide
Thalidomide
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on April 23, 2014